24S-Hydroxycholesterol cerebrosterol

Lutjohann D, Papassotiropoulos A, Bjorkhem I, et al. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 2000 41 195-198. 

L., Diczfalusy, U., Sjovall, X, Einarsson, C. (2001) From brain to bile. Evidence that conjugation and omega-hydroxylation are important for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans./. Biol. Chem.,276(40), 37004-37010. 

Purification of cholesterol through the dibromide completely eliminates cholestanol, 7-dehydrocholesterol, and latho-sterol (A7-cholestenol). The first crop of material from methanol-ether is also free from cerebrosterol (24-hydroxycholesterol) and 25-hydroxycholesterol, a product of autoxidation present in cholesterol that has been stored in the crystalline state for a few years with access to air. When material of highest purity is desired, only first-crop dibromide should be employed, since de-bromination of second-crop material gives sterol melting at 146-147° and giving a positive Beilstein test. 

The C-24 configurations of the isomeric 24-hydroxy-cholesterols have been firmly established5 by chemical correlation with the known 24R,25- and 24S,25-epoxyderivatives, and by the modified Horeau method.6 With the configurations known, differences in 13C n.m.r. spectra and in polarity were used to establish the configurations of the la,24-dihydroxy-derivatives of vitamin D3.5 Cerebrosterol , isolated from brain tissue, is 24S-hydroxycholesterol,6a but the natural 24,25-dihydroxy-vitamin D3 has the (24R) configuration. The C-24 isomeric 24,25-dihydroxy-cholesterols have also been separated and characterized.7... 

The previously described (24S)-24,25-epoxycholesteryl benzoate has been reduced with lithium aluminium hydride-aluminium chloride to give a chromato-graphically separable mixture of 25-hydroxycholesterol (55%) and (24S)-24-hydroxycholesterol (273),133 the configuration of which was determined by the modified Horeau method.135 It is interesting to note that cerebrosterol isolated from brain is (24S)-24-hydroxycholesterol whereas natural 24,25-dihydroxy-vitamin D3... 

A number of oxysterols, which suppress HMGR when added to cell cultures, are natural precursors of cholesterol or products of its metabolism to bile acids or steroid hormones [18]. These sterols include the bile acid intermediates 7a- and 26-hydroxycholesterol, the steroid hormone precursors 20a- and 22R-hydroxycholesterol. 24(s)-hydroxycholesterol (cerebrosterol) was foimd by Kandutch et al [18] that other oxysterol metabolites capable of repressing the reductase may also be produced. Kandutch et al [18] foimd several unidentified oxysterols capable of suppressing activity in extracts of cultured cells. Inhibitory oxysterols are, therefore, produced in all cells that synthesize cholesterol as an end product, as well as in cells that synthesize cholesterol and metabolize it to other steroid products. 

Oxysterols are formed in the first steps of all cholesterol metabolism. The most abundant oxysterol in mammalian brain is 24S-hydroxycholesterol, also known as cerebrosterol. Cerebrosterol is present at a level of 5-50 ng/mg in wet brain and is formed from cholesterol in a cytochrome P450 46A1 (CYP46A1)-catalyzed reaction [56]. CYP46A1 is only expressed in nervous tissue. CYP46A1 also has 25- and 26-hydroxylase activity [57] and low levels of both 25- and 26-hydroxycholesterols are found in brain (1-5 ng/mg) [48,58]. Oxysterol 7a-hydroxylase (CYP7B1) is also expressed in nervous tissue [59] and its substrates 25- and 26-hydroxycholesterols are 7a-hydroxylated by cells of the nervous system and their 7a-hydroxylated products found to be present in brain itself [49,60]. 

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